MuLan-Methyl—multiple transformer-based language models for accurate DNA methylation prediction

Transformer-based language models are successfully used to address massive text-related tasks. DNA methylation is an important epigenetic mechanism, and its analysis provides valuable insights into gene regulation and biomarker identification. Several deep learning–based methods have been proposed to identify DNA methylation, and each seeks to strike a balance between computational effort and accuracy. Here, we introduce MuLan-Methyl, a deep learning framework for predicting DNA methylation sites, which is based on 5 popular transformer-based language models. The framework identifies methylation sites for 3 different types of DNA methylation: N6-adenine, N4-cytosine, and 5-hydroxymethylcytosine. Each of the employed language models is adapted to the task using the “pretrain and fine-tune” paradigm. Pretraining is performed on a custom corpus of DNA fragments and taxonomy lineages using self-supervised learning. Fine-tuning aims at predicting the DNA methylation status of each type. The 5 models are used to collectively predict the DNA methylation status. We report excellent performance of MuLan-Methyl on a benchmark dataset. Moreover, we argue that the model captures characteristic differences between different species that are relevant for methylation. This work demonstrates that language models can be successfully adapted to applications in biological sequence analysis and that joint utilization of different language models improves model performance. Mulan-Methyl is open source, and we provide a web server that implements the approach.